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Cd8a PDF
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Near-infrared (NIR) reflectance spectroscopy was used to determine rapidly and non-destructively the content of
paracetamol in bulk batches of intact Sterwin 500 mg tablets by collecting NIR spectra in the range
1100–2500 nm and using a multiple linear regression calibration method. The developed NIR method gave results
comparable to the British Pharmacopoeia 1993 UV assay procedure, the standard errors of calibration and
prediction being 0.48% and 0.71% m/m, respectively. The method showed good repeatability, the standard
deviation and coefficient of variation for six NIR assays on the same batch on the same day being 0.14 and
0.16% m/m, respectively, while measurements over six consecutive days gave 0.31 and 0.36% m/m, respectively.
Applying the calibration to a parallel test set gave a mean bias of 20.22% and a mean accuracy of 0.45%. The
developed method illustrates how the full potential of NIR can be utilised and how the ICH guidelines which
recommend the validation of linearity, range, accuracy and precision for pharmaceutical registration purposes can
be applied. Duplicate determinations on bulk batches could be performed in under 2 min, allowing the potential
use of the method on-line for real time monitoring of a running production process.
Near-infrared (NIR) absorption is mainly due to overtone and sation (ICH) guidelines12 to the assay. The ICH guidelines
combination vibrations arising from fundamental vibrations in recommend the validation of linearity, range, accuracy and
the mid-infrared region. As these absorptions are weak, NIR precision, both short and long term, for analytical procedures
spectroscopy should be ideally suited for the analysis of intact which are to be used for pharmaceutical registration purposes.
tablets. No sample preparation is required and the method is
non-destructive. Surprisingly, the majority of published appli-
cations of NIR spectroscopy to tablets have not exploited this Experimental
advantage, but used powdered tablets or solutions. Zappala and
Post1 measured meprobamate in tablets after extraction into Materials
chloroform and ranitidine chlorohydrate,2 ranitidine hydro-
chloride3 and cefuroxime acetil4 have all been measured as Forty-five batches of paracetamol tablets were used for the
powdered tablet samples. An early example of an intact tablet study; 35 were normal production batches of Sterwin 500 mg
analysis was a qualitative study5 to identify adulterated aspirin paracetamol tablets (nominal content 84.175% m/m para-
tablets. Quantitative assays based on intact tablets have cetamol) with a nominal diameter of 12.7 mm and thickness of
included the assay of amiodarone chlorohydrate,6 metoprolol,7 3.80–4.15 mm and 10 were development batches (76–92% m/m
SB 216469-S8 and aspirin.9 Recently, we described the paracetamol, i.e., 90–110% of the nominal label content). The
application of transmittance NIR spectroscopy to the analysis of development batches were of the same dimensions as the
individual intact tablets10,11 and compared the effect of various normal production batches but were specially manufactured for
pre-treatments on partial least-squares regression models; this study at a pilot scale on a small scale press, by altering the
experiments involved the measurement of 20 intact tablets with content of paracetamol and the major excipient (starch). The
an analysis time of 10 min per batch. raw materials used were Paracetamol Fine PhEur, Potassium
A problem with intact tablet assays is that normal production Sorbate PhEur, Povidone K-25 PhEur, Pregelatinised Starch
batches do not encompass a sufficiently wide range for setting USNF, Starch Maize PhEur, Stearic Acid BP and Sterilised Talc
up a reliable calibration equation. Tablets which are both under- PhEur, which were of the same specification as those used in the
and overdosed with respect to the analyte need to be produced tablets and were obtained from Sanofi Research Division,
without altering other factors that may affect the assay such as Alnwick Research Centre, Alnwick, Northumberland, UK.
particle size, moisture content and compaction characteristics. All reagents were of analytical-reagent grade and were
Although this complicates the calibration, as compared with obtained from BDH (Poole, Dorset, UK).
powdered tablet assays for which it is easy to prepare standards,
the long-term gains of no sample preparation and the potential
for the use on-line, allowing for real time monitoring of a UV analysis
running production process, make the effort worthwhile.
This paper describes a rapid quantitative assay for the UV measurements were made using a Perkin-Elmer (Beacons-
determination of paracetamol in bulk batches of intact tablets field, Buckinghamshire, UK) Lambda 15 UV/VIS spec-
using diffuse reflectance NIR spectroscopy and multiple trophotometer and 1 cm pathlength matched silica cells. Tablet
wavelength linear regression. Where possible we applied the batches were assayed in duplicate using the following procedure
recommendations of the International Conference on Harmoni- based on the British Pharmacopoeia 199313 assay. The
Fig. 2 Plot of NIR predicted versus UV determined paracetamol content Fig. 3 Plot of NIR predicted versus UV determined paracetamol content
(% m/m) for the calibration set (r = 0.989). (% m/m) for the validation set (r = 0.962).
1 0.1537 0.465 84.63 0.1514 0.462 85.36 85.00 83.15 83.91 83.53
2 0.1558 0.470 84.38 0.1524 0.460 84.43 84.41 83.72 84.39 84.06
3 0.1497 0.450 84.08 0.1529 0.426 84.52 84.30 83.84 83.89 83.87
4 0.1458 0.440 84.41 0.1486 0.450 84.71 84.56 84.20 84.22 84.21
5 0.1495 0.448 83.82 0.1458 0.437 83.84 83.83 83.92 83.94 83.93
6 0.1520 0.454 83.55 0.1457 0.438 84.09 83.82 84.16 84.28 84.22
7 0.1570 0.471 83.92 0.1511 0.454 84.05 83.99 84.02 84.40 84.21
8 0.1494 0.447 83.69 0.1519 0.459 84.52 84.11 83.60 84.19 83.90
9 0.1504 0.452 84.06 0.1488 0.448 84.22 84.14 84.13 84.23 84.18
10 0.1518 0.456 84.03 0.1480 0.445 84.11 84.07 84.24 84.30 84.27
The mean bias [eqn. (11)] and the mean accuracy [eqn. (12)] for Table 2 Analyst intermediate precision data
the parallel test set (n = 10) were determined to be 20.22 and
NIR determinations of paracetamol content (% m/m)
0.45% with standard deviations of 0.63 and 0.48%, re-
spectively. Analyst 1 2 3 4 5 6 Mean
n
Â(
NIR value - UVvalue ) A 84.32 84.51 84.63 84.61 84.64 84.51 84.54
B 84.24 84.25 84.41 84.13 84.00 84.30 84.22
UVvalue
i =1 C 84.29 84.40 84.68 84.28 84.40 84.36 84.40
Mean bias (%) = ¥ 100 (11) D 84.14 84.22 84.02 84.48 84.27 84.33 84.24
n E 84.50 83.88 84.49 83.91 84.11 84.06 84.16
n F 84.70 84.17 84.11 84.36 84.61 83.81 84.29
NIR value - UVvalue
Â
i =1
UVvalue
Mean accuracy (%) = ¥ 100 (12)
n
there was no evidence that the analysts were not equally
precise.
Repeatability